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1.
Nature ; 605(7910): 497-502, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35545679

RESUMEN

Although germline mutation rates and spectra can vary within and between species, common genetic modifiers of the mutation rate have not been identified in nature1. Here we searched for loci that influence germline mutagenesis using a uniquely powerful resource: a panel of recombinant inbred mouse lines known as the BXD, descended from the laboratory strains C57BL/6J (B haplotype) and DBA/2J (D haplotype). Each BXD lineage has been maintained by brother-sister mating in the near absence of natural selection, accumulating de novo mutations for up to 50 years on a known genetic background that is a unique linear mosaic of B and D haplotypes2. We show that mice inheriting D haplotypes at a quantitative trait locus on chromosome 4 accumulate C>A germline mutations at a 50% higher rate than those inheriting B haplotypes, primarily owing to the activity of a C>A-dominated mutational signature known as SBS18. The B and D quantitative trait locus haplotypes encode different alleles of Mutyh, a DNA repair gene that underlies the heritable cancer predisposition syndrome that causes colorectal tumors with a high SBS18 mutation load3,4. Both B and D Mutyh alleles are present in wild populations of Mus musculus domesticus, providing evidence that common genetic variation modulates germline mutagenesis in a model mammalian species.


Asunto(s)
Mutación de Línea Germinal , Mamíferos , Sitios de Carácter Cuantitativo , Alelos , Animales , Variación Genética , Haplotipos/genética , Masculino , Mamíferos/genética , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Mutación , Sitios de Carácter Cuantitativo/genética
2.
Genome Res ; 34(1): 145-159, 2024 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-38290977

RESUMEN

Hundreds of inbred mouse strains and intercross populations have been used to characterize the function of genetic variants that contribute to disease. Thousands of disease-relevant traits have been characterized in mice and made publicly available. New strains and populations including consomics, the collaborative cross, expanded BXD, and inbred wild-derived strains add to existing complex disease mouse models, mapping populations, and sensitized backgrounds for engineered mutations. The genome sequences of inbred strains, along with dense genotypes from others, enable integrated analysis of trait-variant associations across populations, but these analyses are hampered by the sparsity of genotypes available. Moreover, the data are not readily interoperable with other resources. To address these limitations, we created a uniformly dense variant resource by harmonizing multiple data sets. Missing genotypes were imputed using the Viterbi algorithm with a data-driven technique that incorporates local phylogenetic information, an approach that is extendable to other model organisms. The result is a web- and programmatically accessible data service called GenomeMUSter, comprising single-nucleotide variants covering 657 strains at 106.8 million segregating sites. Interoperation with phenotype databases, analytic tools, and other resources enable a wealth of applications, including multitrait, multipopulation meta-analysis. We show this in cross-species comparisons of type 2 diabetes and substance use disorder meta-analyses, leveraging mouse data to characterize the likely role of human variant effects in disease. Other applications include refinement of mapped loci and prioritization of strain backgrounds for disease modeling to further unlock extant mouse diversity for genetic and genomic studies in health and disease.


Asunto(s)
Diabetes Mellitus Tipo 2 , Humanos , Ratones , Animales , Filogenia , Genotipo , Ratones Endogámicos , Fenotipo , Mutación , Variación Genética
3.
Genome Res ; 33(5): 689-702, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37127331

RESUMEN

Short tandem repeats (STRs) are a class of rapidly mutating genetic elements typically characterized by repeated units of 1-6 bp. We leveraged whole-genome sequencing data for 152 recombinant inbred (RI) strains from the BXD family of mice to map loci that modulate genome-wide patterns of new mutations arising during parent-to-offspring transmission at STRs. We defined quantitative phenotypes describing the numbers and types of germline STR mutations in each strain and performed quantitative trait locus (QTL) analyses for each of these phenotypes. We identified a locus on Chromosome 13 at which strains inheriting the C57BL/6J (B) haplotype have a higher rate of STR expansions than those inheriting the DBA/2J (D) haplotype. The strongest candidate gene in this locus is Msh3, a known modifier of STR stability in cancer and at pathogenic repeat expansions in mice and humans, as well as a current drug target against Huntington's disease. The D haplotype at this locus harbors a cluster of variants near the 5' end of Msh3, including multiple missense variants near the DNA mismatch recognition domain. In contrast, the B haplotype contains a unique retrotransposon insertion. The rate of expansion covaries positively with Msh3 expression-with higher expression from the B haplotype. Finally, detailed analysis of mutation patterns showed that strains carrying the B allele have higher expansion rates, but slightly lower overall total mutation rates, compared with those with the D allele, particularly at tetranucleotide repeats. Our results suggest an important role for inherited variants in Msh3 in modulating genome-wide patterns of germline mutations at STRs.


Asunto(s)
Repeticiones de Microsatélite , Sitios de Carácter Cuantitativo , Animales , Ratones , Haplotipos , Ratones Endogámicos C57BL , Ratones Endogámicos DBA
4.
Proc Natl Acad Sci U S A ; 120(17): e2218617120, 2023 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-37068254

RESUMEN

We have developed workflows to align 3D magnetic resonance histology (MRH) of the mouse brain with light sheet microscopy (LSM) and 3D delineations of the same specimen. We start with MRH of the brain in the skull with gradient echo and diffusion tensor imaging (DTI) at 15 µm isotropic resolution which is ~ 1,000 times higher than that of most preclinical MRI. Connectomes are generated with superresolution tract density images of ~5 µm. Brains are cleared, stained for selected proteins, and imaged by LSM at 1.8 µm/pixel. LSM data are registered into the reference MRH space with labels derived from the ABA common coordinate framework. The result is a high-dimensional integrated volume with registration (HiDiver) with alignment precision better than 50 µm. Throughput is sufficiently high that HiDiver is being used in quantitative studies of the impact of gene variants and aging on mouse brain cytoarchitecture and connectomics.


Asunto(s)
Imagen de Difusión Tensora , Microscopía , Ratones , Animales , Imagen de Difusión Tensora/métodos , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Espectroscopía de Resonancia Magnética , Imagen de Difusión por Resonancia Magnética/métodos
5.
Clin Immunol ; 257: 109842, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37981105

RESUMEN

Cardinal features of lupus include elevated B cell activation and autoantibody production with a female sex preponderance. We quantified interactions of sex and genetic variation on the development of autoimmune B-cell phenotypes and autoantibodies in the BXD2 murine model of lupus using a cohort of backcrossed progeny (BXD2 x C57BL/6J) x BXD2. Sex was the key factor leading to increased total IgG, IgG2b, and autoantibodies. The percentage of T-bet+CD11c+ IgD+ activated naive B cells (aNAV) was higher in females and was associated with increased T-bet+CD11c+ IgD- age-related B cells, Fas+GL7+ germinal center B cells, Cxcr5-Icos+ peripheral T-helper cells, and Cxcr5+Icos+ follicular T-helper cells. IFN-ß was elevated in females. Variation in aNAV cells was mapped to Chr 7 in a locus that shows significant interactions between the female sex and heterozygous B/D variant. Our results suggest that activation of naive B cells forms the basis for the female-predominant development of autoantibodies in lupus-susceptible BXD2 mice.


Asunto(s)
Linfocitos B , Lupus Eritematoso Sistémico , Animales , Femenino , Humanos , Masculino , Ratones , Autoanticuerpos , Cruzamientos Genéticos , Centro Germinal , Lupus Eritematoso Sistémico/genética , Ratones Endogámicos C57BL , Linfocitos T Colaboradores-Inductores , Caracteres Sexuales
6.
Int J Mol Sci ; 24(16)2023 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-37628941

RESUMEN

BACKGROUND: Troponin-I interacting kinase encoded by the TNNI3K gene is expressed in nuclei and Z-discs of cardiomyocytes. Mutations in TNNI3K were identified in patients with cardiac conduction diseases, arrhythmias, and cardiomyopathy. METHODS: We performed cardiac gene expression, whole genome sequencing (WGS), and cardiac function analysis in 40 strains of BXD recombinant inbred mice derived from C57BL/6J (B6) and DBA/2J (D2) strains. Expression quantitative trait loci (eQTLs) mapping and gene enrichment analysis was performed, followed by validation of candidate Tnni3k-regulatory genes. RESULTS: WGS identified compound splicing and missense T659I Tnni3k variants in the D2 parent and some BXD strains (D allele) and these strains had significantly lower Tnni3k expression than those carrying wild-type Tnni3k (B allele). Expression levels of Tnni3k significantly correlated with multiple cardiac (heart rate, wall thickness, PR duration, and T amplitude) and metabolic (glucose levels and insulin resistance) phenotypes in BXDs. A significant cis-eQTL on chromosome 3 was identified for the regulation of Tnni3k expression. Furthermore, Tnni3k-correlated genes were primarily involved in cardiac and glucose metabolism-related functions and pathways. Genes Nodal, Gnas, Nfkb1, Bmpr2, Bmp7, Smad7, Acvr1b, Acvr2b, Chrd, Tgfb3, Irs1, and Ppp1cb were differentially expressed between the B and D alleles. CONCLUSIONS: Compound splicing and T659I Tnni3k variants reduce cardiac Tnni3k expression and Tnni3k levels are associated with cardiac and glucose metabolism-related phenotypes.


Asunto(s)
Metabolismo de los Hidratos de Carbono , Miocitos Cardíacos , Animales , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Glucosa , Proteínas Serina-Treonina Quinasas
7.
Neurobiol Dis ; 162: 105581, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34871739

RESUMEN

Mitochondria dysfunction occurs in the aging brain as well as in several neurodegenerative disorders and predisposes neuronal cells to enhanced sensitivity to neurotoxins. 3-nitropropionic acid (3-NP) is a naturally occurring plant and fungal neurotoxin that causes neurodegeneration predominantly in the striatum by irreversibly inhibiting the tricarboxylic acid respiratory chain enzyme, succinate dehydrogenase (SDH), the main constituent of the mitochondria respiratory chain complex II. Significantly, although 3-NP-induced inhibition of SDH occurs in all brain regions, neurodegeneration occurs primarily and almost exclusively in the striatum for reasons still not understood. In rodents, 3-NP-induced striatal neurodegeneration depends on the strain background suggesting that genetic differences among genotypes modulate toxicant variability and mechanisms that underlie 3-NP-induced neuronal cell death. Using the large BXD family of recombinant inbred (RI) strains we demonstrate that variants in Ccnd1 - the gene encoding cyclin D1 - of the DBA/2 J parent underlie the resistance to 3-NP-induced striatal neurodegeneration. In contrast, the Ccnd1 variant inherited from the widely used C57BL/6 J parental strain confers sensitivity. Given that cellular stress triggers induction of cyclin D1 expression followed by cell-cycle re-entry and consequent neuronal cell death, we sought to determine if the C57BL/6 J and DBA/2 J Ccnd1 variants are differentially modulated in response to 3-NP. We confirm that 3-NP induces cyclin D1 expression in striatal neuronal cells of C57BL/6 J, but this response is blunted in the DBA/2 J. We further show that striatal-specific alternative processing of a highly conserved 3'UTR negative regulatory region of Ccnd1 co-segregates with the C57BL/6 J parental Ccnd1 allele in BXD strains and that its differential processing accounts for sensitivity or resistance to 3-NP. Our results indicate that naturally occurring Ccnd1 variants may play a role in the variability observed in neurodegenerative disorders involving mitochondria complex II dysfunction and point to cyclin D1 as a possible therapeutic target.


Asunto(s)
Ciclina D1 , Propionatos , Cuerpo Estriado/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Nitrocompuestos/metabolismo , Nitrocompuestos/toxicidad , Propionatos/metabolismo , Propionatos/toxicidad
8.
Int J Mol Sci ; 23(20)2022 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-36293318

RESUMEN

Air pollution is a known environmental health hazard. A major source of air pollution includes diesel exhaust (DE). Initially, research on DE focused on respiratory morbidities; however, more recently, exposures to DE have been associated with neurological developmental disorders and neurodegeneration. In this study, we investigated the effects of sub-chronic inhalation exposure to DE on neuroinflammatory markers in two inbred mouse strains and both sexes, including whole transcriptome examination of the medial prefrontal cortex. We exposed aged male and female C57BL/6J (B6) and DBA/2J (D2) mice to DE, which was cooled and diluted with HEPA-filtered compressed air for 2 h per day, 5 days a week, for 4 weeks. Control animals were exposed to HEPA-filtered air on the same schedule as DE-exposed animals. The prefrontal cortex was harvested and analyzed for proinflammatory cytokine gene expression (Il1ß, Il6, Tnfα) and transcriptome-wide response by RNA-seq. We observed differential cytokine gene expression between strains and sexes in the DE-exposed vs. control-exposed groups for Il1ß, Tnfα, and Il6. For RNA-seq, we identified 150 differentially expressed genes between air and DE treatment related to natural killer cell-mediated cytotoxicity per Kyoto Encyclopedia of Genes and Genomes pathways. Overall, our data show differential strain-related effects of DE on neuroinflammation and neurotoxicity and demonstrate that B6 are more susceptible than D2 to gene expression changes due to DE exposures than D2. These results are important because B6 mice are often used as the default mouse model for DE studies and strain-related effects of DE neurotoxicity warrant expanded studies.


Asunto(s)
Contaminantes Atmosféricos , Síndromes de Neurotoxicidad , Animales , Masculino , Femenino , Ratones , Emisiones de Vehículos/toxicidad , Contaminantes Atmosféricos/toxicidad , Contaminantes Atmosféricos/análisis , Factor de Necrosis Tumoral alfa , Interleucina-6 , Individualidad , Ratones Endogámicos DBA , Ratones Endogámicos C57BL , Exposición por Inhalación , Citocinas/genética , Citocinas/metabolismo , Genómica
9.
Neuroimage ; 222: 117274, 2020 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-32818613

RESUMEN

Genome-wide association studies have demonstrated significant links between human brain structure and common DNA variants. Similar studies with rodents have been challenging because of smaller brain volumes. Using high field MRI (9.4 T) and compressed sensing, we have achieved microscopic resolution and sufficiently high throughput for rodent population studies. We generated whole brain structural MRI and diffusion connectomes for four diverse isogenic lines of mice (C57BL/6J, DBA/2J, CAST/EiJ, and BTBR) at spatial resolution 20,000 times higher than human connectomes. We measured narrow sense heritability (h2) I.e. the fraction of variance explained by strains in a simple ANOVA model for volumes and scalar diffusion metrics, and estimates of residual technical error for 166 regions in each hemisphere and connectivity between the regions. Volumes of discrete brain regions had the highest mean heritability (0.71 ± 0.23 SD, n = 332), followed by fractional anisotropy (0.54 ± 0.26), radial diffusivity (0.34 ± 0.022), and axial diffusivity (0.28 ± 0.19). Connection profiles were statistically different in 280 of 322 nodes across all four strains. Nearly 150 of the connection profiles were statistically different between the C57BL/6J, DBA/2J, and CAST/EiJ lines. Microscopic whole brain MRI/DTI has allowed us to identify significant heritable phenotypes in brain volume, scalar DTI metrics, and quantitative connectomes.


Asunto(s)
Mapeo Encefálico , Encéfalo/anatomía & histología , Encéfalo/fisiología , Imagen de Difusión Tensora , Animales , Conectoma/métodos , Imagen de Difusión por Resonancia Magnética/métodos , Imagen de Difusión Tensora/métodos , Estudio de Asociación del Genoma Completo , Imagen por Resonancia Magnética/métodos , Ratones
10.
Front Neuroendocrinol ; 52: 195-205, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30576700

RESUMEN

Parental care is found widely across animal taxa and is manifest in a range of behaviours from basic provisioning in cockroaches to highly complex behaviours seen in mammals. The evolution of parental care is viewed as the outcome of an evolutionary cost/benefit trade-off between investing in current and future offspring, leading to the selection of traits in offspring that influence parental behaviour. Thus, level and quality of parental care are affected by both parental and offspring genetic differences that directly and indirectly influence parental care behaviour. While significant research effort has gone into understanding how parental genomes affect parental, and mostly maternal, behaviour, few studies have investigated how offspring genomes affect parental care. In this review, we bring together recent findings across different fields focussing on the mechanism and genetics of offspring effects on maternal care in mammals.


Asunto(s)
Conducta Animal/fisiología , Fenómenos Genéticos/fisiología , Conducta Materna/fisiología , Relaciones Madre-Hijo , Conducta Social , Animales , Humanos
11.
Brain Behav Immun ; 89: 209-223, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32574576

RESUMEN

Gulf War Illness (GWI) is thought to be a chronic neuroimmune disorder caused by in-theater exposure during the 1990-1991 Gulf War. There is a consensus that the illness is caused by exposure to insecticides and nerve agent toxicants. However, the heterogeneity in both development of disease and clinical outcomes strongly suggests a genetic contribution. Here, we modeled GWI in 30 BXD recombinant inbred mouse strains with a combined treatment of corticosterone (CORT) and diisopropyl fluorophosphate (DFP). We quantified transcriptomes from 409 prefrontal cortex samples. Compared to the untreated and DFP treated controls, the combined treatment significantly activated pathways such as cytokine-cytokine receptor interaction and TNF signaling pathway. Protein-protein interaction analysis defined 6 subnetworks for CORT + DFP, with the key regulators being Cxcl1, Il6, Ccnb1, Tnf, Agt, and Itgam. We also identified 21 differentially expressed genes having significant QTLs related to CORT + DFP, but without evidence for untreated and DFP treated controls, suggesting regions of the genome specifically involved in the response to CORT + DFP. We identified Adamts9 as a potential contributor to response to CORT + DFP and found links to symptoms of GWI. Furthermore, we observed a significant effect of CORT + DFP treatment on the relative proportion of myelinating oligodendrocytes, with a QTL on Chromosome 5. We highlight three candidates, Magi2, Sema3c, and Gnai1, based on their high expression in the brain and oligodendrocyte. In summary, our results show significant genetic effects of the CORT + DFP treatment, which mirrors gene and protein expression changes seen in GWI sufferers, providing insight into the disease and a testbed for future interventions.


Asunto(s)
Guerra del Golfo , Síndrome del Golfo Pérsico , Animales , Ratones , Modelos Animales de Enfermedad , Subunidades alfa de la Proteína de Unión al GTP Gi-Go , Isoflurofato , Síndrome del Golfo Pérsico/genética , Transcriptoma
12.
J Neuroinflammation ; 15(1): 86, 2018 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-29549885

RESUMEN

BACKGROUND: Gulf War illness (GWI) is an archetypal, medically unexplained, chronic condition characterised by persistent sickness behaviour and neuroimmune and neuroinflammatory components. An estimated 25-32% of the over 900,000 veterans of the 1991 Gulf War fulfil the requirements of a GWI diagnosis. It has been hypothesised that the high physical and psychological stress of combat may have increased vulnerability to irreversible acetylcholinesterase (AChE) inhibitors leading to a priming of the neuroimmune system. A number of studies have linked high levels of psychophysiological stress and toxicant exposures to epigenetic modifications that regulate gene expression. Recent research in a mouse model of GWI has shown that pre-exposure with the stress hormone corticosterone (CORT) causes an increase in expression of specific chemokines and cytokines in response to diisopropyl fluorophosphate (DFP), a sarin surrogate and irreversible AChE inhibitor. METHODS: C57BL/6J mice were exposed to CORT for 4 days, and exposed to DFP on day 5, before sacrifice 6 h later. The transcriptome was examined using RNA-seq, and the epigenome was examined using reduced representation bisulfite sequencing and H3K27ac ChIP-seq. RESULTS: We show transcriptional, histone modification (H3K27ac) and DNA methylation changes in genes related to the immune and neuronal system, potentially relevant to neuroinflammatory and cognitive symptoms of GWI. Further evidence suggests altered proportions of myelinating oligodendrocytes in the frontal cortex, perhaps connected to white matter deficits seen in GWI sufferers. CONCLUSIONS: Our findings may reflect the early changes which occurred in GWI veterans, and we observe alterations in several pathways altered in GWI sufferers. These close links to changes seen in veterans with GWI indicates that this model reflects the environmental exposures related to GWI and may provide a model for biomarker development and testing future treatments.


Asunto(s)
Encéfalo/metabolismo , Citocinas/metabolismo , Epigénesis Genética/fisiología , Síndrome del Golfo Pérsico/tratamiento farmacológico , Síndrome del Golfo Pérsico/patología , Estrés Psicológico/metabolismo , Animales , Antiinflamatorios/toxicidad , Encéfalo/efectos de los fármacos , Encéfalo/patología , Inhibidores de la Colinesterasa/farmacología , Inmunoprecipitación de Cromatina , Corticosterona/toxicidad , Metilación de ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Epigénesis Genética/efectos de los fármacos , Histonas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Hidrolasas de Triéster Fosfórico/farmacología , Factores de Tiempo
13.
Proc Biol Sci ; 284(1863)2017 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-28954905

RESUMEN

Family members show behavioural strategies predicted to maximize individual fitness. These behaviours depend directly on genes expressed in focal individuals but also indirectly on genes expressed in other family members. However, how sibling and parental behavioural strategies are modified by genes expressed in family members, and to what degree, remains unclear. To answer this question, we have used a split litter design in an experimental population of genetically variable mouse families, and identified loci that indirectly affected sibling and maternal behaviour simultaneously. These loci map to genomic regions that also show a direct effect on offspring behaviour. Directly and indirectly affected traits were significantly correlated at the phenotypic level, illustrating how indirect effects are caused. Genetic variants in offspring that influence solicitation also impacted their siblings' and maternal behaviour. However, in contrast to predictions from sibling competition, unrelated litter mates benefited from increased solicitation. Overall, such indirect genetic effects explained a large proportion of variation seen in behaviours, with candidate genes involved in metabolism to neuronal development. These results reveal that we need to view behavioural strategies as the result of conjoint selection on genetic variation in all interacting family members.


Asunto(s)
Conducta Animal , Sitios Genéticos , Conducta Materna , Ratones/genética , Hermanos , Animales , Femenino , Aptitud Genética , Variación Genética , Fenotipo
14.
BMC Genomics ; 15: 850, 2014 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-25280473

RESUMEN

BACKGROUND: Variation in hippocampal volume has been linked to significant differences in memory, behavior, and cognition among individuals. To identify genetic variants underlying such differences and associated disease phenotypes, multinational consortia such as ENIGMA have used large magnetic resonance imaging (MRI) data sets in human GWAS studies. In addition, mapping studies in mouse model systems have identified genetic variants for brain structure variation with great power. A key challenge is to understand how genetically based differences in brain structure lead to the propensity to develop specific neurological disorders. RESULTS: We combine the largest human GWAS of brain structure with the largest mammalian model system, the BXD recombinant inbred mouse population, to identify novel genetic targets influencing brain structure variation that are linked to increased risk for neurological disorders. We first use a novel cross-species, comparative analysis using mouse and human genetic data to identify a candidate gene, MGST3, associated with adult hippocampus size in both systems. We then establish the coregulation and function of this gene in a comprehensive systems-analysis. CONCLUSIONS: We find that MGST3 is associated with hippocampus size and is linked to a group of neurodegenerative disorders, such as Alzheimer's.


Asunto(s)
Hipocampo/metabolismo , Enfermedades Neurodegenerativas/genética , Animales , Mapeo Cromosómico , Sondas de ADN/metabolismo , Estudio de Asociación del Genoma Completo , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Humanos , Imagen por Resonancia Magnética , Ratones , Ratones Endogámicos C57BL , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/patología , Fenotipo , Sitios de Carácter Cuantitativo , Radiografía
15.
Front Genet ; 14: 1009462, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36923792

RESUMEN

Introduction: Acute myeloid leukemia (AML) is the most common type of leukemia in adults. However, there is a gap in understanding the molecular basis of the disease, partly because key genes associated with AML have not been extensively explored. In the current study, we aimed to identify genes that have strong association with AML based on a cross-species integrative approach. Methods: We used Weighted Gene Co-Expression Network Analysis (WGCNA) to identify co-expressed gene modules significantly correlated with human AML, and further selected the genes exhibiting a significant difference in expression between AML and healthy mouse. Protein-protein interactions, transcription factors, gene function, genetic regulation, and coding sequence variants were integrated to identify key hub genes in AML. Results: The cross-species approach identified a total of 412 genes associated with both human and mouse AML. Enrichment analysis confirmed an association of these genes with hematopoietic and immune-related functions, phenotypes, processes, and pathways. Further, the integrated analysis approach identified a set of important module genes including Nfe2, Trim27, Mef2c, Ets1, Tal1, Foxo1, and Gata1 in AML. Six of these genes (except ETS1) showed significant differential expression between human AML and healthy samples in an independent microarray dataset. All of these genes are known to be involved in immune/hematopoietic functions, and in transcriptional regulation. In addition, Nfe2, Trim27, Mef2c, and Ets1 harbor coding sequence variants, whereas Nfe2 and Trim27 are cis-regulated, making them attractive candidates for validation. Furthermore, subtype-specific analysis of the hub genes in human AML indicated high expression of NFE2 across all the subtypes (M0 through M7) and enriched expression of ETS1, LEF1, GATA1, and TAL1 in M6 and M7 subtypes. A significant correlation between methylation status and expression level was observed for most of these genes in AML patients. Conclusion: Findings from the current study highlight the importance of our cross-species approach in the identification of multiple key candidate genes in AML, which can be further studied to explore their detailed role in leukemia/AML.

16.
Front Toxicol ; 5: 1162749, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37389175

RESUMEN

Of the nearly 1 million military personnel who participated in the 1990-1991 Gulf War, between 25% and 35% became ill with what now is referred to as Gulf War Illness (GWI) by the Department of Defense. Symptoms varied from gastrointestinal distress to lethargy, memory loss, inability to concentrate, depression, respiratory, and reproductive problems. The symptoms have persisted for 30 years in those afflicted but the basis of the illness remains largely unknown. Nerve agents and other chemical exposures in the war zone have been implicated but the long-term effects of these acute exposures have left few if any identifiable signatures. The major aim of this study is to elucidate the possible genomic basis for the persistence of symptoms, especially of the neurological and behavioral effects. To address this, we performed a whole genome epigenetic analysis of the proposed cause of GWI, viz., exposure to organophosphate neurotoxicants combined with high circulating glucocorticoids in two inbred mouse strains, C57BL/6J and DBA/2J. The animals received corticosterone in their drinking water for 7 days followed by injection of diisopropylfluorophosphate, a nerve agent surrogate. Six weeks after DFP injection, the animals were euthanized and medial prefrontal cortex harvested for genome-wide DNA methylation analysis using high-throughput sequencing. We observed 67 differentially methylated genes, notably among them, Ttll7, Akr1c14, Slc44a4, and Rusc2, all related to different symptoms of GWI. Our results support proof of principle of genetic differences in the chronic effects of GWI-related exposures and may reveal why the disease has persisted in many of the now aging Gulf War veterans.

17.
G3 (Bethesda) ; 13(9)2023 08 30.
Artículo en Inglés | MEDLINE | ID: mdl-37405387

RESUMEN

Genetic differences among mammalian hosts and among strains of Mycobacterium tuberculosis (Mtb) are well-established determinants of tuberculosis (TB) patient outcomes. The advent of recombinant inbred mouse panels and next-generation transposon mutagenesis and sequencing approaches has enabled dissection of complex host-pathogen interactions. To identify host and pathogen genetic determinants of Mtb pathogenesis, we infected members of the highly diverse BXD family of strains with a comprehensive library of Mtb transposon mutants (TnSeq). Members of the BXD family segregate for Mtb-resistant C57BL/6J (B6 or B) and Mtb-susceptible DBA/2J (D2 or D) haplotypes. The survival of each bacterial mutant was quantified within each BXD host, and we identified those bacterial genes that were differentially required for Mtb fitness across BXD genotypes. Mutants that varied in survival among the host family of strains were leveraged as reporters of "endophenotypes," each bacterial fitness profile directly probing specific components of the infection microenvironment. We conducted quantitative trait loci (QTL) mapping of these bacterial fitness endophenotypes and identified 140 host-pathogen QTL (hpQTL). We located a QTL hotspot on chromosome 6 (75.97-88.58 Mb) associated with the genetic requirement of multiple Mtb genes: Rv0127 (mak), Rv0359 (rip2), Rv0955 (perM), and Rv3849 (espR). Together, this screen reinforces the utility of bacterial mutant libraries as precise reporters of the host immunological microenvironment during infection and highlights specific host-pathogen genetic interactions for further investigation. To enable downstream follow-up for both bacterial and mammalian genetic research communities, all bacterial fitness profiles have been deposited into GeneNetwork.org and added into the comprehensive collection of TnSeq libraries in MtbTnDB.


Asunto(s)
Mycobacterium tuberculosis , Ratones , Animales , Mycobacterium tuberculosis/genética , Ratones Endogámicos DBA , Ratones Endogámicos C57BL , Sitios de Carácter Cuantitativo , Mutagénesis , Mamíferos/genética
18.
Genes Brain Behav ; 22(6): e12859, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37553802

RESUMEN

Developmental Coordination Disorder (DCD) is a neurodevelopmental disorder of unknown etiology that affects one in 20 children. There is an indication that DCD has an underlying genetic component due to its high heritability. Therefore, we explored the use of a recombinant inbred family of mice known as the BXD panel to understand the genetic basis of complex traits (i.e., motor learning) through identification of quantitative trait loci (QTLs). The overall aim of this study was to utilize the QTL approach to evaluate the genome-to-phenome correlation in BXD strains of mice in order to better understand the human presentation of DCD. Results of this current study confirm differences in motor learning in selected BXD strains and strains with altered cerebellar volume. Five strains - BXD15, BXD27, BXD28, BXD75, and BXD86 - exhibited the most DCD-like phenotype when compared with other BXD strains of interest. Results indicate that BXD15 and BXD75 struggled primarily with gross motor skills, BXD28 primarily had difficulties with fine motor skills, and BXD27 and BXD86 strains struggled with both fine and gross motor skills. The functional roles of genes within significant QTLs were assessed in relation to DCD-like behavior. Only Rab3a (Ras-related protein Rab-3A) emerged as a high likelihood candidate gene for the horizontal ladder rung task. This gene is associated with brain and skeletal muscle development, but lacked nonsynonymous polymorphisms. This study along with Gill et al. (same issue) is the first studies to specifically examine the genetic linkage of DCD using BXD strains of mice.


Asunto(s)
Trastornos de la Destreza Motora , Sitios de Carácter Cuantitativo , Niño , Ratones , Humanos , Animales , Trastornos de la Destreza Motora/genética , Encéfalo , Fenotipo
19.
bioRxiv ; 2023 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-36945430

RESUMEN

Genetic differences among mammalian hosts and Mycobacterium tuberculosis ( Mtb ) strains determine diverse tuberculosis (TB) patient outcomes. The advent of recombinant inbred mouse panels and next-generation transposon mutagenesis and sequencing approaches has enabled dissection of complex host- pathogen interactions. To identify host and pathogen genetic determinants of Mtb pathogenesis, we infected members of the BXD family of mouse strains with a comprehensive library of Mtb transposon mutants (TnSeq). Members of the BXD family segregate for Mtb -resistant C57BL/6J (B6 or B ) and Mtb -susceptible DBA/2J (D2 or D ) haplotypes. The survival of each bacterial mutant was quantified within each BXD host, and we identified those bacterial genes that were differentially required for Mtb fitness across BXD genotypes. Mutants that varied in survival among the host family of strains were leveraged as reporters for "endophenotypes", each bacterial fitness profile directly probing specific components of the infection microenvironment. We conducted QTL mapping of these bacterial fitness endophenotypes and identified 140 h ost- p athogen quantitative trait loci ( hp QTL). We identified a QTL hotspot on chromosome 6 (75.97-88.58 Mb) associated with the genetic requirement of multiple Mtb genes; Rv0127 ( mak ), Rv0359 ( rip2 ), Rv0955 ( perM ), and Rv3849 ( espR ). Together, this screen reinforces the utility of bacterial mutant libraries as precise reporters of the host immunological microenvironment during infection and highlights specific host-pathogen genetic interactions for further investigation. To enable downstream follow-up for both bacterial and mammalian genetic research communities, all bacterial fitness profiles have been deposited into GeneNetwork.org and added into the comprehensive collection of TnSeq libraries in MtbTnDB.

20.
bioRxiv ; 2023 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-37066137

RESUMEN

Pangenome graphs can represent all variation between multiple genomes, but existing methods for constructing them are biased due to reference-guided approaches. In response, we have developed PanGenome Graph Builder (PGGB), a reference-free pipeline for constructing unbi-ased pangenome graphs. PGGB uses all-to-all whole-genome alignments and learned graph embeddings to build and iteratively refine a model in which we can identify variation, measure conservation, detect recombination events, and infer phylogenetic relationships.

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